The computational design of enzymes is a tremendous challenge for both chemistry and biochemistry. The ability to design stable and functional biocatalysts that could operate under different conditions to perform chemical reactions without precedent in nature, allowing the large-scale production of chemicals à la carte, would revolutionise both synthetic, pharmacologic and materials chemistry. Despite the great advances achieved, this highly multidisciplinary area of research is still in its infancy. This chapter describes the ‘inside-out’ protocol for computational enzyme design and both the achievements and limitations of the current technology are highlighted. Furthermore, molecular dynamics simulations have proved to be invaluable in the enzyme design process, constituting an important tool for discovering elusive catalytically relevant conformations of the engineered or designed enzyme. As a complement to the ‘inside-out’ design protocol, different examples where hybrid QM/MM approaches have been directly applied to discover beneficial mutations in rational computational enzyme design are described.